Derivatives of 2h-pyran-3(6h)-ones and preparation thereof

ABSTRACT

THERE ARE DISCLOSED HEREIN 24-HYDROXY-, 24-ACYLOXY-AND 24-ALKOXY-17B,24-EPOXY-21-NORCHOLANE 3,20-DIONE AND 17B,24-EPOXY-19,21-DINORCHOLANE-3,20-DIONE COMPOUNDS AND THEIR CORRESPONDING CHOLANIC ACID Y-LACTONES WITH OPTIONAL DOUBLE BONDS AT POSITIONS 4,5 AND 22,23 AS WELL AS THEIR CORRESPONDING 11-HYDROXY-AND 11-KETO-DERIVATIVES THEREOF. THE COMPOUNDS HAVE ANTIGONADOTROPHIC ACTIVITY AND METHODS FOR THEIR PREPARATION AND USE ARE ALSO DISCLOSED.

3,657,226 DERIVATIVES F ZH-PYRAN-MGID-ONES AND PREPARATION THEREOF Yvon Lefehvre, Pierrefonds, Quebec, Canada, assignor to American Home Products Corporation, New York, N.Y. No Drawing. Continuation-impart of application Ser. No. 5,883, Jan. 26, 1970, which is a continuation-in-part of application Ser. No. 748,196, July 29, 1968. This application Oct. 5, 1970, Ser. No. 78,196

Int. Cl. C07c 173/00 US. Cl. 260-23955 R 25 Claims ABSTRA CT OF THE DISCLOSURE This application is a continuation-in-part of my US. patent application Ser. No. 5,883, filed Jan. 26, 1970, which is a continuation-in-part of my US. patent application Ser. No. 748,196, filed July 29, 1968 now US. Pat. No. 3,547,912.

SUMMARY OF THE INVENTION This invention relates to new and useful derivatives of 175,24-epoxy-2l-norcholanes, to processes used for their preparation and to intermediates used in these processes.

The 17,8,24-epoxy-2l-norcholanes of this invention may be represented by general Formula I in which R and R together represent a ketonic oxygen or R represents hydrogen and R represents the hydroxyl group, an esterified hydroxyl group in which the esterforming group is an aliphatic acid group containing 2 to 7 carbon atoms, or an alkoxy group containing 1 to 3 carbon atoms, R represents two atoms of hydrogen, a hydroxyl group and a hydrogen or a ketonic oxygen, R represents a hydrogen or a methyl; and an optional double bond, signified by a dotted line, may be present at position 4,5 or position 22,23 or at both these positions.

The 175,24-epoxy-2l-norcholanes of this invention possess pharmacologic properties; for example, antigonadotrophic activity. These properties together with their low order of toxicity render the compounds of this invention as useful pharmacologic agents.

DETAILED DESCRIPTION OF THE INVENTION The antigonadotrophic activity of the 175,24-epoxy-21- norcholanes of this invention may be demonstrated in ted States Patent @ifiee 3,657,226 Patented Apr. 18, 1972 standard pharmacological tests, for example, in the test described by C. Revesz and C. I. Chappel, J. Reprod. Fert., 12, 473 (1966).

When the above 17B,24-epoxy-21-norcholane derivatives are employed as antigonadotrophic agents in warmblooded animals, for example, rats, they may be administered orally, alone or in tablets combined with pharmacologically acceptable excipients, such as starch, milk sugar and so forth. They may also be administered orally in the form of solutions in suitable vehicles such as vegetable oils.

The dosage of these 176,24-epoxy-2 l-norcholane derivatives will vary with the particular compound chosen and form of administration. Furthermore, it will vary with the particular host under treatment. Generally, the compounds of this invention are administered at a concentration level that affords the desired pharmacological effect without any deleterious side effects. Those efiective concentration levels are usually obtained with a therapeutic range of 0.1 to mg. per kilo per day with a preferred range of 0.5 to 50 mg. per kilo per day.

The prefer-red starting materials for the compounds of this invention are commercially available steroids of a general, well known type; for example, see L. F. Fieser and M. Fieser, Steroids, Reinhold Publishing Corporation, New York, 1959: These starting materials may be represented by general Formula II in which R and R 4 are as defined above, with an optional double bond at position 4,5 as signified by the dotted line.

These starting materials are converted to their corresponding 17u-[2-fury1]-l7,8-hydroxy steroids of general Formula HI by treatment with 2-furyllithium. During the addition reaction the 3-ketone is protected. Such temporary protection is advantageously afforded by a ketal, enol ether or enamine group. For example, a pyrrolidinyl enamine may be conveniently used to protect the S-ketone of a A -3-ketosteroid and the saturated 3-ketosteroids may be protected by a 3,3-dimethoxy ketal. After the addition of 2-furyllithium to the l7-ketone, the temporary protecting group is conveniently removed by subjecting the reaction product to midly acidic conditions, for example, sodium acetate in acetic acid solution or hydrochloric acid in methanol dilute solution. Preferred conditions for the addition of the 2-furyllithium include the use of an inert solvent, for example, ether, toluene, tetrahydrofuran or hexane, a reaction temperature range of 0 C. to room temperature and reaction times of 15 minutes to three days. However under these preferred conditions an 11- ketone if present will react to some extent with the 2- furyllithium. In this case a shorter reaction time of five to 30 minutes, preferably 15 minutes, preferentially yields the desired 3,11-diketo-17a[2-furyl]-17/8-hydroxysteroid. 2-furyllithium is prepared by the action of n-butyllithium upon 2-bromofuran in ether at room temperature. Alternatively, 2-furyllithium is also obtained by the action of n-butyllithium upon furan in ether at room temperature. In turn, 2-bromofuran is obtained by decarboxylation of 5-bromo-2-furoic acid by the method of A. F. Shepard et al., I. Am. Chem. Soc., 52, p. 2093 (1930).

The above 17ot-[2-furyl]-l7fl-hydroxy steroids are treated with one to two molar equivalents of a hypohalous acid such as, hypobromous or hypochlorous acid or a reagent capable of furnishing the elements of a hypohalous acid upon contact with water. Preferred reagents for this reaction are certain N-haloimides or N-haloamides, for example, N-bromoor N-chlorosuccinimide, or N- chloroor N-bromoacetamide, used with or without small amounts of an acid, preferably perchloric acid; or the reaction may be carried out with an aqueous solution of an alkali metal salt of a hypohalite in contact with acid, such as, for example, sodium hypochlorite and acetic acid. Water must be present and preferred organic solvents include aliphatic and cyclic ethers, such as, for example, diethyl ester, dioxane or tetrahydrofuran; lower aliphatic ketones such as, for example, acetone or methyl ethyl ketone; aromatic hydrocarbons such as, for example, benzene, toluene, or xylene; lower aliphatic esters, such as, for example, the lower alkyl acetates, lower aliphatic carboxylic acids, such as, for example, acetic or butyric acid; lower aliphatic halogenated hydrocarbons such as, for example, chloroform, methylene chloride, or ethylene dichloride; and certain lower aliphatic alcohols such as, for example, methanol and t-butanol. The time of reaction may extend from three minutes to twenty-four hours, and reaction conditions are preferably chosen so as to complete the reaction Within one-half hour. The temperature range at which the reactions may be carried out is from -50 C., with temperatures of about 30 C. being the preferred range.

Alternatively, the above 17a-[2-furyl]-17,6-hydroxy steroids are treated with an organic peracid, such as, for example, peracetic acid, perbenzoic acid, monoperphthalic acid, m-chloroperbenzoic acid, and p-nitroperbenzoic acid. The organic peracid utilized may range in amount from approximately 1.1 molar equivalent to 100 molar equivalents, per mole of steroid starting material. Any practical sol-vent inert to the peracid may be employed. Aliphatic and cyclic ethers, such as, for example, diethyl ether, dioxane, or tetrahydrofuran; lower aliphatic ketones such as, for example, acetone or methyl ethyl ketone; aromatic hydrocarbons such as, for example, benzene, toluene, or xylene; lower aliphatic alcohols, such as, for example, methanol, ethanol, isopropanol, or t-butanol; lower aliphatic acids and their lower alkyl esters such as, for example, acetic acid, ethyl acetate, or butyl acetate; and halogenated hydrocarbons such as, for example, chloroform, methylene chloride, carbon tetrachloride, or ethylene dichloride, are all useful solvents. The time of reaction may extend from 1.5 minutes to 60 hours, with L116 preferred range being from one-half to twenty-four ours.

In this manner, when starting with the 17u-[2-furyl]- l7fl-hydroxy steroids of general Formula III, described above, the corresponding 17,6,24-epoxy-2l-norcholane derivatives of Formula I in which R is hydrogen, R is the hydroxyl group, R and R are as defined above, with an optional double bond at positions 4,5 and a double bond at position 22,23 are obtained.

Treatment of the latter 175,21-epoxy-21-norcholane derivatives of Formula I in which R is the hydroxyl group with an appropriate acid anhydride or acid halide in pyridine affords the corresponding 24-acylated derivatives of Formula I in which R is hydrogen, R is an esterified hydroxyl group in which the ester-forming group is an aliphatic acid containing two to seven carbon atoms, R and R are as defined above, with an optional double bond at position 4,5 and a double bond at position 22,23.

Furthermore, treatment of the same latter 175,24-epoxy- 2l-norcholane derivatives of Formula I in which R is the hydroxyl group with an appropriate lower alkanol in the presence of an acid catalyst, for example, perchloric acid, affords the corresponding 24-ethers of Formula I in which R is hydrogen, R is a lower alkyl, R and R are as defined above, with an optional double bond at position 4,5 and a double bond at position 22,23.

Still furthermore, treatment of the same latter 17,13,24-

epoxy 21 norcholane derivatives of Formula I in which R is the hydroxyl group with a suitable oxidizing agent affords the corresponding ketolactones of Formula I in which R and R together represent a ketonic oxygen, R and R are as defined above, with an optional double bond at position 4,5 and a double bond at position 22, 23. In the case where these latter 17,8,24 epoxy 21- norcholane derivatives of Formula I in which R is the hydroxyl group and R represents two atoms of hydrogen or a ketonic oxygen, then the suitable oxidizing agent may be the hexavalent chromium ion, which may be practically employed, for example, in the form of chromic acid in the presence of sulfuric acid and water, a modification described by A. Bowers et al., J. Chem. Soc., 2548 (1953). However, in the case where these latter 175,24-epoxy 21 norcholane derivatives of Formula I in which R is the hydroxyl group and R represents a hydroxyl group, and a hydrogen hexavalent chromium is not a preferred, suitable oxidizing agent since simultaneous oxidation of the two hydroxyl groups may occur. In this latter case an oxidizing agent for converting allylic alcohols to c p-unsaturated ketones is most suitable; for example, the oxidizing agent, manganese dioxide.

For the preparation of the 17fl,24 epoxy 21 norcholanes of Formula I in which R represents hydrogen and R represents the hydroxyl group, an esterified hydroxyl group as defined above or an alkoxy group containing 1 to 3 carbon atoms, R and R are as defined in the first instance, with an optional double bond at position 4,5 and no double bond at position 22,23, the corresponding 17fl,24 epoxy 21 norcholanes of Formula I in which the double bond at position 22,23 is present, described above, may be reduced by hydrogenation in the presence of a noble metal catalyst, for example, palladium.

For the preparation of the 17fl,24-epoxy-2l-norcholanes of Formula I in which R and R together represent a ketonic oxygen, R and R are as defined in the first instance, with an optional double bond at position 4,5 and no double bond at position 22,23, the corresponding 176,24-epoxy-2l-norcholanes of Formula I in which the double bond at position 22,23 is present, described above, may be reduced in the presence of zinc and acetic acid.

The following examples will illustrate further this invention.

EXAMPLE 1 A mixture of 5a-androstane 3,17 dione g.), methanol (1450 ml.) and p-toluenesulfonic acid (1.8 g.) is stirred for 2 /2 hours. Pyridine (5 ml.) is added and the solid that forms is collected by filtration yielding the ketal, 3,3-dimethoxy-5a-androstan 17 one. The filtrate is evaporated to dryness and the residue crystallized from methanol yielding more of the ketal. Both crops are crystallized together to give material suitable for further use.

A mixture of furan ml.), ether (1000 ml.) and a 1.74 N ethereal solution of n-butyllithium (725 ml.) is stirred for one hour at room temperature. A solution of the 3,3 dimethoxy 5a androstan 17 one, obtained above, in toluene (2430 ml.) is added and the reaction allowed to proceed for 18 hours. Ether is added, the solution washed with water, dried and evaporated yielding crude 3,3 dimethoxy 17a-[2-furyl]-5aandrostan-l7-ol.

A solution of this crude furyl derivative in acetone (1425) is stirred for 1 /2 hours in the presence of oxalic acid (47.5 g.). The acid is neutralized by the addition of a saturated solution of potassium carbonate. The solvent is evaporated and the residue taken up in ethermethylene chloride. The organic solution is further washed with water, dried and evaporated. The residue is crystallized from other and then methylene chloride-methanol TAB LE 1 Corresponding 17a-[2-fu1yl]- Ex, Starting material 17B-hydroxy steroid 2. 11a-hydroxy-fia-androstane- 17a-[2-fu1yl]dictum-dihydroxy- 3,17-dione. a-androstan-3-one.

3 1la-hydroxy-fifi-androstane- 17a-[2-furyll-11a,17B-dihydroxy 3,17-dione. 5fiandrostan-3-one.

4 11fi-hydroxy-fSa-androstane- 17a-[2-furyl]-11fl,17B-dihydroxy- 3,17-dione. 5a-androstan-3-one.

5. 1ld-hydroxy-5B-androstaue- 17a-[2-furyl]-11 8,17B-dihydroxy- 3,17-dione. 5fl-androstan-3-one.

6- 5a-estrane-3J 7-dione 17a-[2-fuwl]-17B-hydroxy-5aestran-3 one. 7 5B es crane-3, 17-dione 17a-[2-furyl]-17B-hydroxy-5B- estran-S-one.

8 lla-hydroxy-M-estrane 17a-[2'furyl]-11a,17fi-dihydroxy- 3,17-dione. 5a-estran-3-one.

Corresponding 17a-[2-lury1]- 17B-hydroxy steroid Starting material EXAMPLE 16 1711 [2' furyl] 17B hydroxyandrost 4 en 3 one (III: R =H, R =CH and double bond at position Pyrrolidine (100 ml.) is added to a boiling solution of androst-4-ene-3,17-dione (100 g.) in methanol (1000 ml.). After cooling, the solid that had formed is filtered, washed with methanol and dried, yielding 3-[1-pyrrolidinyl]-androsta-3,5-dien-17-one.

A solution of furan (136 g.), ether (2200 ml.) and a 2.12 N ethereal solution of n-butyllithium (870 ml.) is stirred at room temperature for one hour. A solution of the enamine (110 g.), obtained above, in toluene (4400 ml.) is added and the mixture stirred overnight at room temperature. Ether and water are added. The organic solution is further washed to neutrality, dried and evaporated to dryness.

The crude product (130 g.) is dissolved in benzene (4000 ml.) and the solution refluxed for 4 hours in the presence of acetic acid (260 ml), sodium acetate (390 g.) and water (390 ml.).

After cooling the solution is washed with a dilute sulfuric acid solution, sodium bicarbonate and water, dried and evaporated. The residue is treated twice with charcoal and crystallized from acetone-hexane giving 6 the title compound, M.P. 192193 C-, [0c] =99.3 a),

A 225 m (e:

17,200) and 242 m (e=17,500)

By following the procedure of Example 16 but using an equivalent amount of the appropriate starting material listed in Table III instead of androst-4-ene-3,17-dione, the corresponding 17a-[2-furyl]-17[3-hydroxy steroids, listed in Table III are obtained.

TABLE III Corresponding 17a-[2'- M.P., hydroxy]-175-hydroxy Ex. Starting material steroid C.

17- 11B'l1ydroxyandr0st-4- 17a-[2-1uryl]-1 15,17-dihy- 179-180 ene-3,17-dione. droxyandrost4-en-3-one. 18. Estr-4-ene-3,17-dione 17a-[2-furyl]-17B-hydroxy 126 127 estr-4-en-3-one.

EXAMPLE 19 In the same manner as described for Example 16 but using an equivalent amount of 11u-hydroxyandrost-4-ene- 3,17-dione, 11cc hydroxyestr 4 ene 3,17 dione or hydroxyestr 4 ene 3,17 dione instead of androst 4 ene 3,17 dione, 17a [2' furyl]- 11u,175 dihydroxyandrost 4 en 3 one, 1711 [2- furyl] 1104,1713 dihydroxyestr 4 en 3 one and 17a- [2' furyl] 115,175 dihydroxyestr 4 en 3 one may be obtained, respectively.

EXAMPLE 20 17w[2-furyl]-17fi-hydroxyandrost-4-ene-3,1l-dione (III: R =O, R =CH and a double bond at position 4,5)

Pyrrolidine (118 ml.) is added to a boiling solution of androst-4-ene-3,11,17-trione (118 g.) in methanol (3180 ml.). The mixture is cooled and the solid collected. The solid is washed with methanol and dried, yielding 3-(1- pyrrolidinyl) -3-androsta-3 ,5-diene-11,17-dione.

A solution of furan (72 g.), ether (2500 ml.) and a 1.90 N ethereal solution of n-butyllithium (280 ml.) is stirred for one hour at room temperature. A solution of the enamine (132 g.), obtained above, in benzene (2500 ml.) is added and the mixture stirred for 15 minutes at 0 C. The reaction mixture is washed with water, dried and evaporated yielding crude 17a-[2-furyl]-17,8-hydroxy-3 l-pyrrolidinyl -androsta-3,5-dien-l l-one.

This crude furyl derivative g.) is dissolved in benzene (2500 ml.). The solution is refluxed for 4 hours in the presence of sodium acetate (275 g.), Water (375 ml.) and acetic acid (250 ml.). The cooled solution is washed with dilute sulfuric acid, sodium bicarbonate and water to neutrality. After drying the solution, the solvent is removed under reduced pressure. The residue is crystallized from acetone, containing a small quantity of hexane to yield the title compound, M.P. 232234 C., [@1 +1603 (CHClg).

EXAMPLE 21 In the same manner as described for Example 20 but using an equivalent amount of estr-4-ene-3,11,17-trione instead of androst-4-ene-3,11,17-trione, 17a-[2-furyl]- 1 7fi-hydroxyestr-4-ene-3,ll-dione may be obtained.

EXAMPLE 22 17fi,24-epoxy 24 hydroxy-21-nor-5a,17a-chol-22-ene-3, 20-dione (I: R -H, R =OH, R =H R =CH and a double bond at position 22,23).

Procedure A.A solution of m-chloroperbenzoic acid (87%39.5 g.) in chloroform (1290 ml.) is added at room temperature over a period of 20 minutes to a solution of 17a-[2'-furyl]-17B-hydroxy-5a-androstan 3 one (64.5 g.), prepared as described in Example 1, in chloroform (1290 ml.). After stirring for 4 /2 hours, the solution is washed thoroughly with sodium bicarbonate and water, dried and evaporated to dryness. The residue is chromatographed on silica gel. The product is eluted with 25% 7 ethyl acetate-benzene. Crystallization from acetone alfords the title compound, M.P. 2162l8 C., [a] =+69.3 (CHCI A 216 mu (e=8780) and 350 m (6 91) Procedure B.The title compound may be obtained also in the following manner. N-bromosuccinimide (1.0 g.) is added by portions to a mixture of 17u-[2'-furyl]-l7/3- hydroxy-a-androstan-3-one (2.0 g.), prepared as described in Example 1, in methanol (216 ml.) and water (21 ml.). The mixture is stirred for five minutes. Water is added; the mixture is extracted with ether and the ether solution is washed with water, dried and evaporated. Work-up of the resultant residue in the same manner is described above for Procedure A affords the title compound, identical to the product of Procedure A In the same manner as described in above Procedures A or B but using an equivalent amount of 17a-[2-furyl]- 17fi-hydroxy-5fi-androstan-3-one, prepared as described in Example 1, instead of 17a-[2'-furyl]-l7B-hydroxy-5aandrostan-3-one, 17,8,24-epoxy-24 hydroxy 21 nor-5 8, 17u-chol-22-ene-3,20-dione, M.P. 222223 C.,

[a] =+89.6 (CHCI is obtained.

is filtered, washed with acetone to yield the title compound, M.P. 241-243 C., [a] +139 (CHCl A232? 238 mu (6: 17,300) after crystallization from methylene chloride-acetone.

Procedure B.The title compound may be obtained also in the following manner. N-bromosuccinimide (220 mg.) is added by portions to a mixture of 17u-[2'-furyl]- 17fl-hydroxyandrost-4-en-3-one (400 mg.), prepared as described in Example 16, in methanol (20 ml.) and water (16 ml.). After stirring for ten minutes at room temperature, the solution is poured into a saturated solution of sodium bicarbonate and extracted with ether. The ether is washed to neutrality, dried and evaporated to dryness. The residue is crystallized successively with ether then acetone yielding the title compound, identical to the product obtained in above Procedure A.

By following the Procedures A or B of Example 37 but using an equivalent amount of the appropriate starting material, the 17a-[2-furyl]-17,S-hydroxy steroids described in Examples 17 and 18 instead of 17a-[2'-furyl]- 175-hydroxyandrost-4-en-3-one, the compounds of Formula I, listed in Table V, are obtained. In each case the appropriate starting material is noted by the example in which it is prepared.

By following the Procedures A or B of Example 22 but using an equivalent amount of the appropriate starting material, the 1711-[2-furyl]-17B-hydrox steroids de- TABLE V scribed in Examples 2 to 15, instead of l7u[2-furyl]- Numberof 17fl-hydroxy-5a-androstan-3-one, the compounds of Forexampie mula I, listed in Table IV, may be obtained. In each case l g a g the source of the appropriate starting material is noted Ex material Product C. by the example in which it is prepared. 38"" 17 173 1 3 2,; 1 g% g 199400 0 0a iene-, none. 39.... 18 l7B,24-epoxy-24-hydroxy-19,21-dinor-17a- 263-237 TABLE IV chola-4,22-diene-3.20-dione.

Number of example 323315 EXAMPLE Exam? material Pmduct 40 In the same manner as described for Procedures A or 23 2 l7fl,l.l24-epoxy-11a.2 -dihydroxy-2l-nor-5a,17a- B of Example 37 but usig an equivalent amount of c o1-22-ene-3,20- ionc. I 24 3 WQHDOXM1amtdihydmxWHOFEB',7w 17:1 [2 furyl] 11u,1"7B dihydroxyandrost 4 en 3 one, 170: ehol 22-ene-3,20-dine. [2 -furyl]-11a,l7/8-dihydroxyestr-4-ene-3-one or 17a-[2 25 4 "iiifi ii g b iiiiti furyl] 11p,17fi dihydroxyestr-4-en-3-one, described in 2a 1m ai ox g 3 2 4 11h drox -ai-nor-sa,17.1- Example 19, 17-[2-furyl]-17fi-hydr0xyandr0st-4-e -3, c 0- -ene-, 10119. 27 6 17B24 epoxy g4 hydmxy mygbdmopsayum ll-dione, described in Example 20, or 171 [2 furyl] 173 c 2ene-3,20-dione. hydroxyestr-4-ene3,ll-dione, described in Example 21, 28 7 fiflgggggflggggi instead of 17a-[2'-furyl]-17B-hydroxyandrost-4-en-3-one, 29 8 175, po y y y- -d the following compounds of Formula I may be obtained,

5a,17a-chol-22-ene-3,QO-dione. r S l 30 9 1Lgbi-7ep0irlyil212a,24-dil5y%r0xy-19,21-dinor- 6 Pac We t a-c o- -ene-3, 0- lone. 31 10 l7q 24-iiptgxgilw,agglziydroxy-ltl,2l-dinor-5a igs-31 315 gfif y ylCl-C 10- -ene-, 10110. I eneone, 32 11 17/7,?4-e oxy-11fi,2t-d1h drox -19,21-d1nor-5B,

17a,clihl-22-enc-320-dioue. y fl, p yy y- 33 12 l7fl,2/i-Ii(ix%;4:hydroxy-21nor-5a,l7a-el10l-22 17 h -4 22-die -3 2Q-di n ene- ,2 none. 34 1a 1vg zrn x g r a am -ai-iror-sai'ra-choi- I P yl Y 3? Y- -ene- ,11, rione. 17a-chola-4 22-diene-3 2 dione 3' 14 1' ,244 OX -24-h dr -19,2l-d' =5 ,1"

o h01 t3s3c.3,1120.3%, mm a 175,24-BPOXY-24-hYdIOXY-Zl-DOI-l'loc-ChOlH: 36 15 17fl,24-epoxy-24'hydroxy-1tl,2l-dinor-5B,l7a- 4 22 di 3 1lawn-h d chol-22-enc-3,11,20-triouc.

EXAMPLE 37 17 8,24-epoxy 24 hydroxy-21-nor-17a-chola-4,22-diene- 3,20-dione (I: R :H, R =CH, R =H R =CH and double bonds at positions 4,5 and 22,23)

1713,24-epoxy-24-hydroxy-19,21-dinor-l7a-chola- 4,22-diene-3,11,20-trione.

EXAMPLE 41 l713,24-epoxy-24-hydroxy-2l-nor-17a-chola 4,22 diene- 3,11,20-trione 24-acetate (I: R =H, R =OCOCH R =O, R =CH and double bond at positions 4,5 and 22,23

A solution of 1713,24epoxy-24-hydroxy-2l-nor-17achola-4,22-diene-3,l1,20-trione (10 g.), prepared as described in Example 40, in pyridine m1.) and acetic anhydride (100 ml.) is stirred at room temperature for one hour. The solution is poured into ice-water and the resulting solid is collected and washed with water. This solid is dissolved in a mixture of ether and methylene chloride. The solution is washed with dilute sulfuric acid, sodium bicarbonate and water to neutrality. After drying the solution, the solvents are removed under reduced pressure. The residue is chromatographed on silica gel. The eluant is 25% ethyl acetate-benzene. Fractions 6-9 are crystallized from methanol and then acetone-hexane to yield the title compound, M.P. 181-183 C., [a] =+206.8 (CHClg).

EXAMPLE 42 By following the procedure of Example 41 and using the appropriate acylating agent, for instance, acetic, propionic, butyric, hexanoic or heptanoic anhydride, together with the appropriate starting material selected from the products of Examples 22 to 40, inclusive, then the corresponding 24-acylates, for instance, the 24-acetates, the 24-propionates, the 24-butyrate's, the 24-hexanoates or the 24-heptanoates, of the products of Examples 22-40 may be obtained.

EXAMPLE 43 176,24-epoxy-24-hydroxy-2l-nor-17a-chola 4,22 diene- 3,20-dione 24-methyl ether (I: R =H, R =OCH R =H R =CH and double bonds at positions 4,5, and 22,23)

A suspension of 173,24-epoxy-24-hydroxy-2l-nor-17achola-4,22-dien-3,ZO-dione (500 mg), methanol (20 ml.) and a 70% solution of perchloric acid (0.5 ml.) is stirred at room temperature for 60 minutes. The solid goes rapidly in solution. The solution is diluted with water and extracted with ether. The ether is washed with sodium bicarbonate and water to neutrality, dried and evaporated to dryness. The residue is purified by chromatography on silica gel. Elution with benzene-ethyl acetate (9:1) and crystallization from acetone-hexane affords the title compound, M.P. 135-138 C.

EXAMPLE 44 By following the procedure of Example 43 and using the appropriate lower alkanol, for instance, methanol, ethanol or propanol, together with the appropriate starting material selected from the products of Examples 22 to 40, inclusive, then the corresponding 24-lower alkoxy derivatives, for instance the 24-methyl ethers, the 24-ethyl ethers, or the 24-propyl ethers, of the products of Examples 22-40 may be obtained.

EXAMPLE 45 17,3-hydroxy-3,20-dioxo-21-nor-5a,17a-ch0l-22-enoic acid fi-lactone (I: R and R =O, R =H R =CH and a double bond at position 22,23)

An 8 N chromic acid solution (37 ml., see A. Bowers et al., cited above) is added over a period of 10 minutes to a stirred solution of 17[3,24-epoxy-24-hydroxy-2l-nor- 5a,17a-chol-22-ene-3,20-d.ione (28.2 g.), prepared as described in Example 22, acetone (1410 ml.). After stirring for 20 minutes, the excess oxidant is destroyed by the addition of isopropanol. Water is added and most of the acetone is evaporated under reduced pressure. The solid is collected, washed with water and dried. Crystallization from methylene chloride-methanol affords the title compound, M.P. 246-247 C., [a] =+l58 (CHCl A223? 219 m (e=11,900) and 360 m (e= 156) In the same manner but using an equivalent amount of 173,24-epoxy 24 hydroxy-21-nor-5B,17a-chol-22-ene-3, 20-dione, prepared as described in Example 22, instead of 173,24-epoxy 24 hYdIOXY-Zl-HOI-Sa,17oc-Ch01-22-en6-3, 20-dione, 17fi-hydroxy-3,20- dioxo-21-nor-5B,l7a-chol-22- enoic acid fi-lactone, M.P. 276-279 C., [a]==+15l.3 (CHCl is obtained.

By following the procedure of Example 45 but using an equivalent amount of the appropriate starting material, the compounds of Formula I in which R is the hydroxyl group and R is two hydrogen atoms or a ketonic oxygen, instead of 17,6,24-epoxy-24-hydroxy-21-nor-5a, 17a-chol-22-ene-3,20-dione, the corresponding compounds of Formula I in which R and R both represent a ketonic oxygen, listed in Table VI, may be obtained. In each case the source of the appropriate starting material is noted by the example in which it is prepared.

TABLE VI Number of example describing starting material Example Product EXAMPLE 5 2 l7fl-hydroxy-3,20-dioxo-21-nor-17a-chola 4,22 dienoic acid B-lactone (I: R and R =O, R =H R =CH and double bonds at positions 4,5 and 22,23)

An 8 N chromic acid solution (57 ml., see A Bowers et al., cited above) is added to a stirred suspension of 17p, 24 epoxy-24-hydroxy-2l-nor-l7a-chola 4,22 diene-3, 20-dione (43 g.), prepared as described in Example 37, in acetone (2100 ml.). The mixture is stirred for 20 minutes and then the excess oxidant is destroyed by isopropanol. The acetone is evaporated and the residue suspended in water. The solid is collected, washed with water and dried, yielding the title compound, of suitable quality for further use.

Part of the material is purified by chromatography on silica gel. The product is eluted with 10% ethyl acetatebenzene. Crystallization from acetone-hexane yielded the pure title compound, M.P. l92-l93 C., [a] =|-Z51.4,

AEtOH max.

EXAMPLE 5 3 17,8 hydroxy-3,11,20-trioxo-21-nor 17a chola-4,22-

dienoic acid fi-lactone (I: R R and R =O, R =CH and double bonds at positions 4,5 and 22,23)

An 8 N chromic acid solution (84 ml., see A. Bowers et al., cited above) is added to a 17 8,24-epoxy-24-hydroxy 21-nor-l7a-chola-4,22-diene-3,11,20-trione (52 g.), prepared as described in Example 40, in acetone (3640 ml.). The mixture is stirred for 2 hours at room temperature. Isopropanol (50 ml.) is added to destroy the excess oxidant. Water is added and most of the acetone is removed under reduced pressure. The resultant solid is collected, washed with water and dried. This solid is chromatographed on silica gel. Elution with 35% ethyl acetatebenzene and crystallization of the eluate from methylene chloride-methanol gives the title compound, M.P. 261- 262 C. [0:1 +309.7 (CHCl In the same manner but using an equivalent amount of 1713,24 epoxy-24-hydroxy-19,21-dinor-l7e-chola-4,22- diene-3,ll,20-trione, prepared as described in Example 40, instead of 17,8,24-epoxy-24-hydroxy-21-nor-17u-chola- 4,22-diene-3,l 1,20-trione, 17,8-hydroxy-3,11,20-trioXo-l9, 2l-dinor-l7a-chola-4,22-dienoic acid e-lactone is obtained.

1 1 EXAMPLE s4 11B,17B-dihydroxy-3,20-dioxo-2l-nor 17oz chola-4,22-

dienoic acid ii-lactone (I: R and R =O, R =OH and H, R =CH and double bonds at positions 4,5 and 22,23)

A mixture of 17 8,24 epoxy-11,8,24-dihydroxy-21-nor- 17a-chola-4,22-diene-3,20-dione (8 g.), prepared as described in Example 38, chloroform (320 ml.) and activated manganese dioxide (40 g.) are refluxed for 15 minutes. After cooling, the inorganic material is collected on a filter and washed with chloroform. The filtrate is evaporated to dryness, The residue is chromatographed on silica gel. The fractions eluted with 35% ethyl acetatebenzene are crystallized from a mixture of chloroformacetone-hexane to give the title compound, MP. 270- 273 C., [a] =+295.8 (CHCl By following the procedure of Example 54 but using an equivalent amount of the appropriate starting material, the compounds of Formula I in which R is the hydroxyl group and R is a hydroxyl group and a hydrogen, instead of 17,8,24-epoxy-11 8,24-dihydroxy-21-nor-17ot-chola-4,22- dione-3,20-dione, the corresponding compounds of Formula I in which R and R both represent a ketonic oxygen, listed in Table VII, may be obtained. In each case the source of the appropriate starting material is noted by the example in which it is prepared.

TABLE VII Number of example describing starting Example material Product 55 23 lla,l7fidihydroxy-3,20-di0xo-21-nor-5a,17a-

chol-22cnoie acid fi-lactone. 56 24 11a,17Bdihydroxy-3,20-dioxo-21-nor-5B,l7a-

chol-22-enoic acid 8-1act0ne. 57 25 1i(3,17fi-dihydroxy-3,20-di0xo21-nor-5a,17a-

chol-22renoic acid rS-lactcne. 58 2G 115,17fl-dihy droxy-3.20-dioxo'21-nor-5fi,17a-

chol-22-enoic-acid a-lactonc. 59 29 1101,17B-dihydroxy-3,20-dioxo-l9,21-dinor-5a,

17a-chol-22-enoic acid 5-lactone. G0. 30 11oz,178-dihydroxy-3,20-di0x0-19,21-dinor-5B,

17aehol-22enoic acid fi lactone. G1 31 116,17fi-dihydrxy-3,20-dioxo-19,2l-dinoraJ7a-ch01-22-enoic acid a-lactone. 62 32 116,17fl-dihydroxy-3.20-dioxo-l9,21-dinor- EXAMPLE 63 In the same manner as described for Example 54 but using an equivalent amount of 173-,24-epoxy-11,9,24-dihydroxy-19,21-dinor-17u-ch0la- 4,22-diene-3 ,20-dione,

17,3,24-epoxy-1 1a,24-dihydroxy-21-nor-17a-chola- 4,22-diene-3,20-dione or 17,8,24-epoxy-1 1a,24-dihydroxy-19,21-dinor-17a-cho1a- 4,22-diene-3,20-dione,

prepared as described in Example 40, instead of g.) is hydrogenated at room temperature and normal pressure for 30 minutes. The catalyst is collected on a filter pad and the filtrate is concentrated to dryness. The residue is subjected to chromatography on silica gel. Elution with 30% ethyl acetate-benzene and recrystallization of the eluate from methylene chloride-acetone affords the title product,

NMR (CDCl 218, 235, 325 Hz.

By following the procedure of Example 64 but using an equivalent amount of the appropriate starting material, the compounds of Formula I in which R represents hydrogen, R represents the hydroxyl group, an esterified hydroxyl group as defined above, or an alkoxy group containing 1-3 carbon atoms, R and R are as defined in the first instance with an optional double bond at position 4,5 and a double bond at position 22,34 instead of 175,24 epoxy 24 hydroxy 21- nor-17a-ch1oa-4,22-diene-3,20 dione, the corresponding compound of Formula I in which the bond at position 22,23 is saturated, listed in Table VIII, are obtained. In each case the source of the appropriate starting material is noted by the Example in which it is prepared.

TABLE VIII Number of example describing starting material Product 175,24-ep0xy-24-hydr0xy-21-nor-5a,17a-

eh0lane-3,20-di0nc. 176,244ipoxy-24-hydroxy-21-nor-5fl,17a-ch0lanc- 3,20di0ne. l7fi,24-ep0xy-1la,24-dihydroxy-21-n0r-5a,17a-

cholane-3,20-dionc. 17B,24-cpoxy-1la,24-dihydroxy-21-n0r-5fl,17a-

cholane-3,20dione. l7B.24-epoxy-11fl,24-dihydroxy-2l-nor-5a,l7a-

cholane-3,20-dione. 17B,24-epoxy415,24'dihydroxy-12-nor-513,17a-

eh olanc-3,20 dione. 17H,24-cpoxy-24-hydroxy-19,21-dinor-5a,17a-

ch0lane-3,20-dionc. 17B.24-epoxy-24hydroxy-19,21-dinor-5B,17a-

cholane-3,20-di0ne. 175,?Aepoxy-11a,24-dihydroxy-19,21-dinor- 5m,17a-ch0lane-3,2(Hiione. 175,24-epoxy-11a,24-dihydroxy-19,21-dinor- 5B,17ach01ane-3,20-dione. 17B,24-epoxy-11B,2A-dihydroxy-l9,21-dinor- 5a,17a-(:hOlal1G-3,20-(1i0l10. 17B,24-epoxy-116,2A-dihydroxy-19,2l-dinor- 5fl,17a-ch0lane3,20-dione. 175,24-ep0xy-24-hydroxy-21-nor-M,17a-cholane- 3,11,10-t1'ione. 17fl,24-epoxy-24-hydroxy-21mot-55,17a-

cholane-3,11,20-trionc 17B 24-cpoxy-24-hydroxy-19,21-dinor-5a,17a-

c 0lane-3,11,20-tnone. 17B,24epoxy24-hydroxy-19,21dinor-53,1702- cholane-3,11,20-tiione. 175,24-epoxy-11B,24-dihydroxy-12-nor-17achol-4-ene-3,20-dionc. 17B,24-epoxy-24-hydroxy-l9,21-dinor-17achol-4-cnc-3,2)-di0ne. 175,24-cp0xy-24-hydroxy-21-nor-17a-chol-4-cne- 3,11,20-triono 24-acetatc. 175,24-epoxy-24-hydroxy-21-nor-17a-chol-4- one-3,20dionc 24 methyl ether.

Example 176,24 epoxy :,24 dihydroxy-21-nor-17u-chol-4- ene 3,20 dione, 1713,24-epoxy-11a,24-dihydroxy-19,21- dinor 17oz chol-4-ene-3,20-dione, 17/3,24-epoxy-11;3,24- dihydroxy- 19,21-dinor-17a-chol-4-ene-3 ,20-dione, 1713,24- epoxy 24-hydroxy-21-nor-17a-ch0l-4-ene-3,11,20-trione, 17fi,24 epoxy-24-hydroxy-19,21-dinor-17a-chol 4 ene- 3,11,20-trione, the 24 acylates, for instance, the 24- acetates, the 24-propionates, the 24-butyrates, the 24- hexanoates, or the 24-heptanoates, of the product of Examples 64 to 82, and the 24-methyl ethers, the 24-ethyl ethers and the 24-propyl ethers of the products of Examples 6482, may be obtained by following the procedure of Example 64 but using an equivalent amount of the corresponding derivatives containing the double bond at position 22,23, described respectively in Example 40,

13 42 and 44, instead of 17p,24-epoxy-24-hydroxy-2l-norl7a-chola-4,22-diene-3,20-dione.

EXAMPLE 86 17,3 hydroxy 3,20 dioxo 21 nor 55,17 cholanoic acid fi-lactone I: R and R'*-=O, R =H R =OH and 22,23 bond is saturated) A mixture of 17,8-l1ydroxy-3,20-dioxo-21-nor-5/3,17achol-22-enoic acid fi-lactone (19.6 g.), prepared as described in Example 45, acetic acid (980 ml.) and zinc dust (98. g.) is stirred for 75 minutes at room temperature. The zinc is collected, washed with acetic acid and water. The filtrate is diluted with water. The resulting solid is collected, washed with water and dried. This solid is crystallized from methylene chloride-methanol giving the title compound of suitable quality for further use. Part of this solid is chromatographed on silica gel. Elution with 30% ethyl acetate-benzene aifords the pure title compound, M.P. 234-236 C., [u] =|-|-E54.8.

In the same manner but using an equivalent amount of 17,9 hydro'xy 3,20-dioxo 21 nor-5a-chol-22-enoic acid ti-lactone, described in Example 45, instead of 17,8- hydroxy 3,20 dioxo 21 nor-5,8-chol-22-enoic acid fi-lactone, 17,9 7 hydroxy 3,20 dioxo 21 nor 5a,17ucholanoic acid a-lactone, M.P. 216-217 C., [01], {+635 (CHCl is obtained.

By following the procedure of Example 86 but using an equivalent amount of the appropriate starting material, the compounds of Formula I in which R and R =O, instead of 17 3 l 1ydro xy 3,20 dioxo 21-nor-5l3-chol-22- enoic acid fi-lactone, the compounds of Formula I in which R and R and the 22,23 bondis saturated, listed in Table IX, may be obtained. In each case the source of the appropriate starting material is noted by the example in which it is prepared.

TABLE IX Number of exam is describ ng starting Example material Product 87 46 17B-hydroxy-3,20-dioxo-l9,21-dinor-5a,l7a-

cholanoic acid Hactone. 88 47 17B-hydroxy-3,2041ioxo-19,2l-dinor-5B,17a-

cholanoic acid fi-lactone. 89 48 l7B-hydroxy-3,11,20-trioxo21-nor-5a,17a

cholanoic acid fi-lactone. 90 49 17B-hydroxy-3,1l,20-trioxo-2l-nor-5B,17a-

17a-ch0lanic acid 6-lacton'e. 91 50 17B-l1ydroxy-3,11,20-trioxo-19,21-dinor-5a,17a-

cholanoic acid 6-lactone.- 92 51 17B-hydroxy-3,11,20-trioxo-19,21-dinor-5fi,l7a-

cholanoic acid laetone. 93 55 11a,17B-dihydroxy-3,20-di0xo-21-onr-5a,17a-

cholanoic acid 5-lactone. 94 56 11a,17B-dihydroxy-3,20diox0-21-r10r-5fl,17a-

cholanoic acid fi-lactone. 95 57 11B,17B-dihydroxy-3,20dioxo-21-nor-5a,17a-

cholanoie acid a-lactone. 96 58 11B,17fl-dihydroxy-3,20-dioxo-21-nor-5 ,17a-

cholanoic acid fi-lactone. 97 59 11a,l7fl-dihydroxy-3,20-dioxo-19,21-dinorcholanoic acid B-lactone. 98 60 11a,176-dihydroxy-3,20-dioxo-19,21-dinor- 5B,17a-cholanoic acid 6-lactone. 99 61 116,17B-dihydroxy-3,20-dioxo-19,21-dinor- 5a-17a-cholanoic acid a-lactone. 100 62 11B,l7Bdihydroxy-3,20dioxo-l9,21-dinor- 6,9,17B-cho1anoic acid B-lactone.

EXAMPLE 1 01 17B hydroxy 3,20 dioxo 19,21 dinor 17a. chol- 4-enoic acid fi-lactone (I: R and R =O, R =H R =H, double bond at position 4,5 and 22,23 bond is saturated).

A mixture of 17fl-hydroxy-3,20-dioxo-19,21-dinor-17achola-4,22-dienoic acid a-lactone (18 g.), prepared as described in Example 52, acetic acid (900 ml.) and zinc dust (90 g.) is stirred at room temperature for 60 minutes. The zinc is collected and washed with acetic acid and water. The filtrate is diluted with water. The resulting solid is collected, washed with water and dried. This solid is chromatographed on Silica gel. The fractions 14 eluted with 25% ethyl acetate-benzene are combined and crystallized from methylene chloride-methanol to yield the pure title compound, M.P. 226-227 C., [04], Hj89.8,

A33? 240 m (e=17,500)

By following the procedure of Example 101 but using an equivalent amount of the appropriate starting material, the compounds of Formula I in which R and 11 :0, instead of 17,8-hydroxy-3,20dioxo-19,21-dinor-17a-chola- 4,22-dienoic acid a-lactone, the compounds of Formula I in which R and R =O and the 22,23 bond is saturated, listed in Table X, may be obtained. In each case the source of the appropriate starting material is noted by the Example in which it is prepared.

In the same manner as described for Example 101 but using an equivalent amount 11a,17/3-dihydroxy-3,20- dioxo-2l-nor-17a-chola-4,22-dienoic acid a-lactone, 11a, 17fi-dihydroxy-3,20 dioxo-19,21-dinor-17a chola-4,22- dienoic acid fi-lactone, 11p,17 3-dihydroxy-3,20-dioxo-19, 2l-dinor-17a-ch0la-4,22-dien0ic acid 6-lactone, described in Example 63, or 17;8-hydroxy-3,11,20-trioxo-19,21- dinor-l7ot-chola-4,22-dienoic acid a-lactone, described in Example 53, instead of 17B-hydroxy-3,20-dioxo-19,21- dinor-l7a-chola-4,22-dienoic acid a-lactone, the following compounds of Formula I in which R and R =O and the 22,23 bond is saturated may be obtained, respectively:

1 1 a,17fl-dihydroxy-3,20-dioxo-2l-nor- 17a-cho1-4-enoic acid a-lactone,

1 1a,17fl-dihydroxy-3,20-dioxo-19,21-dinor-17a-chol-4- enoic acid 5-lactone,

1 15,17;3-dihydroxy-3,20-dioxo-19,21-dinor-17a-chol-4- enoic acid -lactone, and

17 ,B-hydroxy-3,1 1,20-trioxo- 19,2 1-dinor-17 ot-ch01-4- enoic acid fi-lactone.

I claim:

1. A compound selected from those of the formula wherein R and R together represent ketonic oxygen, or R represents hydrogen and R represents hydroxyl, an esterified hydroxyl in which the ester-forming group is an aliphatic acid group containing from two to seven carbon atoms, or an alkoxy group containing from one to three carbon atoms; R represents two atoms of hydrogen, hydroxyl and a hydrogen atom, or ketonic oxygen; R represents hydrogen or methyl; and an optional double bond, signified by a dotted line, may be present at position 4,5 or at position 22,23, or at both said positions.

2. 17,8,24-epoxy-24 hydroxy 2l-I1015a,17a-ChOl-22- ene-3,20-dione, as claimed in claim 1.

3. 175,24-epoxy-24-hydroxy 21 nor-5,8,1h-chol-22- ene-3,20-dione, as claimed in claim 1.

4. 175,24-epoxy-24-hydroxy 21 nor 17a-chola-4,22- diene-3,20-dione, as claimed in claim 1.

5. 17,3,24-epxy-115,24-dihydroxy 21 nor-17a-chola- 4,22-diene-3,20-dione, as claimed in claim 1.

6. 17fi-24-epoxy-24-hydroxy-19,2l dinor-17a-chola-4, 22-diene-3,20-dione, as claimed in claim 1.

7. 1713,24-epoxy-24-hydroxy 21-nor 17a-chola-4,22- diene3,11,20-tri0ne, as claimed in claim 1.

8. 175,24-ep0xy-24-hydroxy 21 nor-17a-chola-4,22- diene-3,1l,20-trione 24-acetate, as claimed in claim 1.

9. 17fi,24-epoxy-24-hydroxy 21 nor-17a-chola-4,22- diene-3,20-dione 24-methyl ether, as claimed in claim 1.

10. 17B-hydroxy-3,20-dioxo-2-nor 504,174: chol-22- enoic acid a-lactone, as claimed in claim 1.

11. 17;8-hydr0xy-3,20-dioxo-21 nor 5fl,17oc-ChOl-22- enoic acid 6-lactone, as claimed in claim 1.

12. 17B-hydroxy-3,20-dioxo-2l-nor 17oz cho1a-4,22- dienoic acid B-lactone, as claimed in claim 1.

13. 175-hydroxy-3,l1,20-trioxo-21 nor 17u-chola- 4,22-dienoic acid fi-lactone, as claimed in claim 1.

14. 11 8,17fl-dihydroxy-3,20-dioxo 21-nor-17a-cl1ola- 4,22-dienoic acid fi-lactone, as claimed in claim 1.

15. 175,24-epoxy-24-hydroxy-21 nor 17a-chola-4- ene-3,20-dione, as claimed in claim 1.

16. 17B-hydroxy-3,20-dioxo-2l-nor 513,1718-cholanoic acid a-lactone, as claimed in claim 1.

17. 17fl-hydroxy-3,20-dioxo-2l nor 5a,l7u-cholanoic acid fi-lactone, as claimed in claim 1.

18. 17,8-hydroxy-3,20-dioxo-19,21 dinor 17a-cholan- 4-enoic fi-lactone, as claimed in claim 1.

19. A compound selected from those of the formula wherein R represents two atoms of hydrogen, a hydroxyl and one atom of hydrogen, or ketonic oxygen; R represents hydrogen or methyl; and an optional double bond may be present at position 4,5 as signified by the dotted line extending between these positions.

20. 17a-[2'-fury1]-17/3 hydroxy 5u-androstan-3-one, as claimed in claim 19.

21. 17a-[2-furyl]-17fl hydroxy 5B-androstan-3-one, as claimed in claim 19.

22. 17a-[2'-furyl]-17p hydroxyandrost 4-en-3-one, as claimed in claim 19.

23. 17a-[2'-fnryl]-11fl,17 dihydroxyandrost 4-en-3- one, as claimed in claim 19.

24. 17a-[2'-furyl]-17p hydroxyestr 4-en-3-one, as claimed in claim 19.

25. 17a-[2'-furyl]-17 8 hydroxyandrost 4-ene-3,11- dione, as claimed in claim 19.

References Cited UNITED STATES PATENTS 3,432,486 3/1969 Minato 260-2l0.5

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

$04050 UNITED STATES PATENT OFFICE @ERTHEQATE @F @RETKN Patent No. 3 57 22'5 Dated April 18 1972 fl Yvon Lefeovre It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, Formula I should read o- 50 I "UNITED STATES PATENT OFFICE CER'NFICATE 0F QQRRECTIN Patent No. 3,657,226 Dated Avril 18 1972 Inventor(s Yvon Le febvre 2 It is certified that errof appears in the above-identified patent and that said Letters Patent are Qereby corrected as shown below:

. Column 15; Claim 10, line 18 3,ZO-dtLoxo-Z-nm: should read ----3,2O-dioxo-2l-nor-- l 7 Column 15, Claim 16, line 31 "zl-nor-sa,lm-cholanoic" should read --2l-nor-58,l7a-cholanoic-- Column 16, Formula of Claim 19, should read Signed and sealed this 10th day of April 1973.

(SEAL) a Attest:

EDWARD M.PLETCHER,JR, V ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

